Hypophosphatemic rickets is a disorder characterized by hypophosphatemia, defective intestinal absorption of calcium, and rickets or osteomalacia unresponsive to vitamin D. It is usually hereditary. Symptoms are bone pain, fractures, and growth abnormalities. Diagnosis is by serum phosphate, alkaline phosphatase, and 1,25-dihydroxyvitamin D3 levels. Treatment is oral phosphate plus calcitriol.

Familial hypophosphatemic rickets is usually inherited as an X-linked dominant trait; other familial patterns occur but are rarer.

Pathophysiology

The observed abnormality is decreased proximal renal tubular resorption of phosphate, resulting in renal phosphate wasting and hypophosphatemia. This defect is due to circulating factors called phosphatonins. The principle phosphatonin in hereditary hypophosphatemic rickets is FGF-23. Decreased intestinal calcium and phosphate absorption also occurs. Deficient bone mineralization is due to low phosphate levels and osteoblast dysfunction rather than to the low calcium and elevated parathyroid hormone (PTH) levels as in calcipenic rickets (see Vitamin D Deficiency and Dependency). Because 1,25-dihydroxyvitamin D3 levels are normal to slightly low, a defect in conversion is presumed; hypophosphatemia would normally cause elevated 1,25-dihydroxyvitamin D3 levels.

A form of hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is known to occur due to mutations in the proximal tubule type 2c sodium-phosphate cotransporter. Defective phosphate transport and hypophosphatemia in this case result in appropriately increased 1,25-dihydroxyvitamin D3 levels, thus leading to hypercalciuria.

Symptoms and Signs

The disease manifests as a spectrum of abnormalities, from hypophosphatemia alone to growth retardation and short stature to severe rickets or osteomalacia. Children usually present after they begin walking, with bowing of the legs and other bone deformities, pseudofractures (ie, x-ray findings in osteomalacia that may represent areas of prior stress fractures that have been replaced by inadequately mineralized osteoid vs areas of bony erosions), bone pain, and short stature. Bony outgrowth at muscle attachments may limit motion.

Rickets of the spine or pelvis, dental enamel defects, and tetany that occur in dietary vitamin D deficiency are rarely present in hypophosphatemic rickets.

Patients with HHRH may present with nephrolithiasis and/or nephrocalcinosis.

Diagnosis

Urinary phosphate and creatinine levels (for calculation of the tubular reabsorption of phosphate)

Bone x-rays

Serum phosphate levels are depressed, but urinary phosphate excretion is large. Serum calcium and PTH are normal, and alkaline phosphatase often is elevated. Hypophosphatemia-induced stimulation of calcitriol production does not occur. Typically, calcidiol levels are normal, whereas calcitriol levels are normal to low. In calcipenic rickets, hypocalcemia is present, hypophosphatemia is mild or absent, and urinary phosphate is not elevated.

Treatment

Oral phosphate and calcitriol

Treatment of hypophosphatemic rickets consists of neutral phosphate solution or tablets. Starting dose in children is 10 mg/kg (based on elemental phosphorus) po qid. Phosphate supplementation lowers ionized calcium concentrations and further inhibits calcitriol conversion, leading to secondary hyperparathyroidism and exacerbating urinary phosphate wasting. Therefore, vitamin D is given as calcitriol, initially 5 to 10 ng/kg po bid. This, however, is not the case with HHRH, where 1,25-dihydroxyvitamin D3 levels are elevated and dosing with calcitriol can be detrimental.

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